Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model

While levodopa therapy for Parkinson's disease (PD) may effectively relieve motor symptoms, many of the cognitive deficits experienced by PD patients (and in animal models of PD) are not effectively managed by this treatment. In contrast, previous work has shown positive effects of nicotinic therapies on cognition in PD models. The present study evaluated the effects of levodopa, nicotine and the nicotinic acetylcholine receptor agonist SIB-1553A alone and in combination on cognition in a non-human primate model of early PD. Three adult male Rhesus monkeys, previously administered low doses of the neurotoxin MPTP over several months to produce cognitive deficits, were trained to perform a modified spatial delayed response task in which the attentional demands of the task were manipulated by varying the duration of the cue presentation while keeping the memory demands of the task low and constant. Task performance was assessed after administration of levodopa, nicotine ditartrate, or SIB-1553A and after administration of drug combinations. Animals performed normally when task attentional load was low (i.e., with long cue durations) but performance was significantly impaired on short cue duration trials. Levodopa further impaired performance on short cue duration trials and induced a deficit on long cue duration trials. Nicotine and SIB-1553A improved performance on short cue trials and when co-administered with levodopa, counteracted levodopa-induced deficits. These results confirm that nicotinic therapies may be useful for treating cognitive deficits associated with PD and suggest that negative effects of levodopa on cognition may be amenable to correction with adjunctive nicotinic therapies.